RESUMEN
Maxillofacial bone defects can severely impact quality of life by impairing physiological functions such as chewing, breathing, swallowing, and pronunciation. Polyether ether ketone (PEEK) is commonly used for the repair of maxillofacial defects due to its mechanical adaptability, while its osteogenic properties still need refinement. Herein, we have utilized the piezoelectric effect exhibited by barium titanate (BTO) under low-intensity pulsed ultrasound (LIPUS) to develop an ultrasound responsive PEEK (PDA@BTO-SPEEK, PBSP) through the mediating effect of polydopamine (PDA), for repairing maxillofacial bone defects. After modification by PDA@BTO, PBSP possesses better hydrophilicity, which is conducive to cell growth and adhesion. Simultaneously, by virtue of the piezoelectric characteristics of BTO, PBSP obtains a piezoelectric coefficient that matches the bone cortex. Notably, when PBSP is stimulated by LIPUS, it can generate stable electricity and effectively accelerate the osteogenic differentiation of osteoblasts through the regulation of the Piezo1-induced calcium (Ca2+) influx and Akt/GSK3ß/ß-catenin pathway. In addition, PBSP presents satisfactory therapeutic effects in rat skull defect models, and its osteogenic efficiency can be further improved under LIPUS stimulation with high tissue penetration. Collectively, PBSP + LIPUS exhibits great potential as a promising alternative strategy for the repair of maxillofacial bone defects.
Asunto(s)
Benzofenonas , Glucógeno Sintasa Quinasa 3 beta , Cetonas , Osteogénesis , Polietilenglicoles , Polímeros , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , beta Catenina , Animales , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Polímeros/química , Osteogénesis/efectos de los fármacos , Ratas , Polietilenglicoles/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Cetonas/química , Cetonas/farmacología , beta Catenina/metabolismo , Diferenciación Celular/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Ondas Ultrasónicas , Indoles/química , Indoles/farmacología , Masculino , Transducción de Señal/efectos de los fármacos , Cráneo/efectos de los fármacos , Titanio/química , Titanio/farmacología , Regeneración Ósea/efectos de los fármacosRESUMEN
Polycyclic polyprenylated acylphloroglucinols (PPAPs) comprise a large group of compounds of mostly plant origin. The best-known compound is hyperforin from St. John's wort with its antidepressant, antitumor and antimicrobial properties. The chemical synthesis of PPAP variants allows the generation of compounds with improved activity and compatibility. Here, we studied the antimicrobial activity of two synthetic PPAP-derivatives, the water-insoluble PPAP23 and the water-soluble sodium salt PPAP53. In vitro, both compounds exhibited good activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Both compounds had no adverse effects on Galleria mellonella wax moth larvae. However, they were unable to protect the larvae from infection with S. aureus because components of the larval coelom neutralized the antimicrobial activity; a similar effect was also seen with serum albumin. In silico docking studies with PPAP53 revealed that it binds to the F1 pocket of human serum albumin with a binding energy of -7.5 kcal/mol. In an infection model of septic arthritis, PPAP23 decreased the formation of abscesses and S. aureus load in kidneys; in a mouse skin abscess model, topical treatment with PPAP53 reduced S. aureus counts. Both PPAPs were active against anaerobic Gram-positive gut bacteria such as neurotransmitter-producing Clostridium, Enterococcus or Ruminococcus species. Based on these results, we foresee possible applications in the decolonization of pathogens.
Asunto(s)
Cetonas , Staphylococcus aureus Resistente a Meticilina , Compuestos de Espiro , Animales , Humanos , Ratones , Antibacterianos/farmacología , Antibacterianos/química , Enterococcus faecium/efectos de los fármacos , Cetonas/química , Cetonas/farmacología , Larva/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Mariposas Nocturnas/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
In order to discover a new antibiotic drug with better or similar activity of the already existing drugs, a series of novel cobalt(II) complexes with ß-diketonate as ligands is synthesized and tested on four strains of bacteria and four species of fungi. All compounds showed notable antimicrobial activity against all tested strains. More importantly, some cobalt(II) complexes displayed greater activity than ketoconazole. It is important to notice that on the tested strains Mucor mucedo and Penicillium italicum complex 2B showed five times better activity compared to ketoconazole, while complex 2D had two times better activity on Penicillium italicum strain compared to ketoconazole. Moreover, investigations with bovine serum albumin were performed. Investigations showed that the tested complexes have an appropriate affinity for binding to bovine serum albumin. In addition, the molecular docking study was performed to investigate more specifically the sites and binding mode of the tested cobalt(II) complexes with ß-diketonate as ligands to bovine serum albumin, tyrosyl-tRNA synthetase, topoisomerase II DNA gyrase, and cytochrome P450 14 alpha-sterol demethylase. In conclusion, all the results indicated the great prospective of the novel cobalt complexes for some potential clinical applications in the future.
Asunto(s)
Cobalto , Complejos de Coordinación , Simulación del Acoplamiento Molecular , Albúmina Sérica Bovina , Cobalto/química , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/metabolismo , Bovinos , Animales , Cristalografía por Rayos X , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Antibacterianos/metabolismo , Bacterias/efectos de los fármacos , Estructura Molecular , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/síntesis química , Cetonas/química , Cetonas/farmacología , Cetonas/metabolismoRESUMEN
BACKGROUND/AIM: A major challenge in treating soft-tissue sarcoma is the development of drug resistance. Eribulin, an anti-tubulin agent, is used as a second-line chemotherapy for patients with unresectable or metastatic soft-tissue sarcoma. However, most patients with advanced soft-tissue sarcoma are resistant to eribulin and do not survive. Recombinant methioninase (rMETase) targets the fundamental and general hallmark of cancer, methionine addiction, termed the Hoffman Effect. The present study aimed to show how much rMETase could increase the efficacy of eribulin on eribulin-resistant fibrosarcoma cells in vitro. MATERIALS AND METHODS: HT1080 human fibrosarcoma cells were exposed to step-wise increasing concentrations of eribulin from 0.15-0.4 nM to establish eribulin-resistant HT1080 (ER-HT1080). ER-HT1080 cells were cultured in vitro and divided into four groups: untreated control; eribulin treated (0.15 nM); rMETase treated (0.75 U/ml); and eribulin (0.15 nM) plus rMETase (0.75 U/ml) treated. RESULTS: The IC50 of eribulin on ER-HT1080 cells was 0.95 nM compared to the IC50 of 0.15 nM on HT1080 cells, a 6-fold increase. The IC50 of rMETase on ER-HT1080 and HT1080 was 0.87 U/ml and 0.75 U/ml, respectively. The combination of rMETase (0.75 U/ml) and eribulin (0.15 nM) was synergistic on ER-HT1080 cells resulting in an inhibition of 80.1% compared to eribulin alone (5.0%) or rMETase alone (47.1%) (p<0.05). rMETase thus increased the efficacy of eribulin 16-fold on eribulin-resistant fibrosarcoma cells. CONCLUSION: The present study showed that the combination of eribulin and rMETase can overcome high eribulin resistance of fibrosarcoma. The present results demonstrate that combining rMETase with first- or second-line therapy for soft-tissue sarcoma has the potential to overcome the intractable clinical problem of drug-resistant soft-tissue sarcoma.
Asunto(s)
Liasas de Carbono-Azufre , Resistencia a Antineoplásicos , Fibrosarcoma , Furanos , Cetonas , Humanos , Cetonas/farmacología , Furanos/farmacología , Liasas de Carbono-Azufre/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Fibrosarcoma/tratamiento farmacológico , Fibrosarcoma/patología , Línea Celular Tumoral , Proteínas Recombinantes/farmacología , Antineoplásicos/farmacología , Sinergismo Farmacológico , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Policétidos PoliéteresRESUMEN
Today, it would be difficult for us to live a full life without polymers, especially in medicine, where its applicability is constantly expanding, giving satisfactory results without any harm effects on health. This study focused on the formation of hexagonal domains doped with AgNPs using a KrF excimer laser (λ=248â¯nm) on the polyetheretherketone (PEEK) surface that acts as an unfailing source of the antibacterial agent - silver. The hexagonal structure was formed with a grid placed in front of the incident laser beam. Surfaces with immobilized silver nanoparticles (AgNPs) were observed by AFM and SEM. Changes in surface chemistry were studied by XPS. To determine the concentration of released Ag+ ions, ICP-MS analysis was used. The antibacterial tests proved the antibacterial efficacy of Ag-doped PEEK composites against Escherichia coli and Staphylococcus aureus as the most common pathogens. Because AgNPs are also known for their strong toxicity, we also included cytotoxicity tests in this study. The findings presented here contribute to the advancement of materials design in the biomedical field, offering a novel starting point for combating bacterial infections through the innovative integration of AgNPs into inert synthetic polymers.
Asunto(s)
Antibacterianos , Benzofenonas , Escherichia coli , Nanopartículas del Metal , Pruebas de Sensibilidad Microbiana , Polietilenglicoles , Polímeros , Plata , Staphylococcus aureus , Plata/química , Plata/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Polímeros/química , Polímeros/farmacología , Escherichia coli/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Polietilenglicoles/química , Polietilenglicoles/farmacología , Benzofenonas/química , Benzofenonas/farmacología , Nanopartículas del Metal/química , Propiedades de Superficie , Cetonas/química , Cetonas/farmacología , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Humanos , Equipos y Suministros/microbiología , Tamaño de la PartículaRESUMEN
N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.
Asunto(s)
Antineoplásicos , Etilenos , Compuestos Heterocíclicos , Cetonas , Humanos , Línea Celular Tumoral , Etilenos/química , Etilenos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Cetonas/química , Cetonas/farmacología , Cetonas/síntesis química , Relación Estructura-Actividad , Histona Desacetilasas/metabolismo , Simulación del Acoplamiento Molecular , Ensayos de Selección de Medicamentos Antitumorales , Acetales/química , Acetales/farmacología , Acetales/síntesis química , Proteínas RepresorasRESUMEN
Glioblastoma tumors are the most aggressive primary brain tumors that develop resistance to temozolomide (TMZ). Eribulin (ERB) exhibits a unique mechanism of action by inhibiting microtubule dynamics during the G2/M cell cycle phase. We utilized the T98G human glioma cell line to investigate the effects of ERB and TMZ, both individually and in combination. The experimental groups were established as follows: control, E5 (5 nM ERB), T0.75 (0.75 mM TMZ), T1 (1.0 mM TMZ), and combination groups (E5+T0.75 and E5+T1). All groups showed a significant decrease in cell proliferation. Apoptotic markers revealed a time-dependent increase in annexin-V expression, across all treatment groups at the 48-hour time point. Caspase-3, exhibited an increase in the combination treatment groups at the 48-hour mark. Transmission electron microscopy (TEM) revealed normal ultrastructural features in the glioma cells of the control group. However, treatments induced ultrastructural changes within the spheroid glioblastoma model, particularly in the combination groups. These changes included a dose-dependent increase in autophagic vacuoles and apoptotic morphology of the cells. In conclusion, the similarity in the mechanism of action between ERB and TMZ suggests the potential for synergistic effects when combined. Our results highlight that this combination induced severe damage and autophagy in glioma spheroids after 48 hours.
Asunto(s)
Apoptosis , Neoplasias Encefálicas , Proliferación Celular , Furanos , Glioblastoma , Cetonas , Temozolomida , Humanos , Temozolomida/farmacología , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/ultraestructura , Furanos/farmacología , Cetonas/farmacología , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/ultraestructura , Proliferación Celular/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Microscopía Electrónica de Transmisión , Autofagia/efectos de los fármacos , Policétidos PoliéteresRESUMEN
Eribulin (ERI), clinically utilized for locally advanced or metastatic breast tumors, has shown potential links to the immune system. Notably, the cGAS-STING pathway, a key component of innate immunity, has gained prominence. Yet, limited reports explore ERI's effects on the cGAS-STING pathway. Additionally, the nuclear presence of cGAS remains poorly understood. This study uniquely delves into ERI's impact on both the cytosolic cGAS-STING pathway and nuclear cGAS. ERI enhances nuclear localization of cGAS, resulting in hyper-activation of the cGAS-STING pathway in triple-negative breast cancer cells. Reduction of cGAS heightened both cell proliferation and ERI sensitivity. In clinical data using ERI in a neo-adjuvant setting, patients with low cGAS cases exhibited reduced likelihood of achieving pathological complete response after ERI treatment. These findings illuminate the potential of cGAS and IFNß as predictive biomarkers for ERI sensitivity, providing valuable insights for personalized breast cancer treatment strategies.
Asunto(s)
Núcleo Celular , Furanos , Cetonas , Nucleotidiltransferasas , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/genética , Nucleotidiltransferasas/metabolismo , Femenino , Cetonas/farmacología , Núcleo Celular/metabolismo , Núcleo Celular/efectos de los fármacos , Línea Celular Tumoral , Furanos/farmacología , Proliferación Celular/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Transducción de Señal/efectos de los fármacos , Policétidos PoliéteresRESUMEN
Natural and synthetic polymeric materials, particularly soft and hard tissue replacements, are paramount in medicine. We prepared calcium-incorporated sulfonated polyether-ether ketone (SPEEK) polymer membranes for bone applications. The bioactivity was higher after 21 days of immersion in simulated body fluid (SBF) due to calcium concentration in the membrane. We present a new biomaterial healing system composed of calcium and sulfonated polyether ether ketone (Ca-SPEEK) that can function as a successful biomaterial without causing inflammation when tested on bone marrow cells. The Ca-SPEEK exhibited 13 ± 0.5% clot with low fibrin mesh formation compared to 21 ± 0.5% in SPEEK. In addition, the Ca-SPEEK showed higher protein adsorption than SPEEK membranes. As an inflammatory response, IL-1 and TNF-α in the case of Ca-SPEEK were lower than those for SPEEK. We found an early regulation of IL-10 in the case of Ca-SPEEK at 6 h, which may be attributed to the down-regulation of the inflammatory markers IL-1 and TNF-α. These results evidence the innovative bioactivity of Ca-SPEEK with low inflammatory response, opening venues for bone applications.
Asunto(s)
Materiales Biocompatibles , Células de la Médula Ósea , Calcio , Polímeros , Factor de Necrosis Tumoral alfa , Animales , Ratones , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Polímeros/química , Polímeros/farmacología , Calcio/metabolismo , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Benzofenonas/química , Benzofenonas/farmacología , Inflamación/tratamiento farmacológico , Polietilenglicoles/química , Polietilenglicoles/farmacología , Cetonas/química , Cetonas/farmacología , Ensayo de Materiales , Interleucina-1/metabolismo , Interleucina-10/metabolismoRESUMEN
Polyetheretherketone (PEEK), renowned for its exceptional mechanical properties and bio-stability, is considered a promising alternative to traditional metal-based implants. However, the inferior bactericidal activity and the limited angiogenic and osteogenic properties of PEEK remain the three major obstacles to osseointegration in vivo. To overcome these obstacles, in this work, a versatile heterostructured nanocoating was conceived and equipped on PEEK. This nanocoating was designed to endow PEEK with the ability of photo-activated pathogen disinfection, along with enhanced angiogenesis and osteogenesis, effectively addressing the triple-barrier challenge towards osseointegration. The crafted nanocoating, encompassing diverse nutritional metal elements (Fe3+, Mg2+, and Sr2+) and a fusion peptide adept at promoting angiogenesis and osteogenesis, was seamlessly decorated onto PEEK. The engineered implant exhibited an antibacterial activity of over 94% upon near-infrared illumination by virtue of the photothermal conversion of the polyphenol nanocoating. Simultaneously, the decorated hierarchical nanocoatings synergistically promoted cellular adhesion and proliferation and up-regulated angiogenesis-/osteogenesis-associated cytokine expression in endothelial/osteoblast cells, resulting in superior angiogenic differentiation and osteoinductive capability in vitro. Moreover, an in vivo assay in a rabbit femoral defect model revealed that the decorated implant can achieve ameliorative osseointegrative fixation. Collectively, this work offers a practical and instructive clinical strategy to address the triple-barrier challenge associated with PEEK-based implants.
Asunto(s)
Antibacterianos , Benzofenonas , Oseointegración , Polietilenglicoles , Polímeros , Animales , Oseointegración/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Conejos , Polímeros/química , Polímeros/farmacología , Polietilenglicoles/química , Humanos , Osteogénesis/efectos de los fármacos , Prótesis e Implantes , Péptidos/química , Péptidos/farmacología , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Staphylococcus aureus/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteoblastos/citología , Osteoblastos/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Cetonas/química , Cetonas/farmacología , Proliferación Celular/efectos de los fármacos , Línea Celular , Escherichia coli/efectos de los fármacos , Adhesión Celular/efectos de los fármacosRESUMEN
Polyether-ether-ketone (PEEK) is clinically used as a bio-implant for the healing of skeletal defects. However, the osseointegration of clinical-sized bone grafts remains limited. In this study, surface-porous PEEK was created by using a sulfonation method and a metal-polysaccharide complex MgCS was introduced on the surface of sulfonated PEEK to form MgCS@SPEEK. The as-prepared MgCS@SPEEK was found to have a porous surface with good hydrophilicity and bioactivity. This was followed by an investigation into whether MgCS loaded onto sulfonated PEEK surfaces could promote osseointegration and angiogenesis. The in vitro results showed that MgCS@SPEEK had a positive effect on reducing the expression levels of inflammatory genes and promoting osteogenesis and angiogenesis-related genes expression levels. Furthermore, porous MgCS@SPEEK was implanted in critical-sized rat tibial defects for in vivo evaluation of osseointegration. The micro-computed tomography evaluation results revealed substantial bone formation at 4 and 8 weeks. Collectively, these findings indicate that MgCS@SPEEK could provide improved osseointegration and an attractive strategy for orthopaedic applications.
Asunto(s)
Benzofenonas , Sulfatos de Condroitina , Cetonas , Oseointegración , Osteogénesis , Polietilenglicoles , Polímeros , Animales , Polímeros/química , Ratas , Cetonas/química , Cetonas/farmacología , Polietilenglicoles/química , Oseointegración/efectos de los fármacos , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacología , Osteogénesis/efectos de los fármacos , Magnesio/farmacología , Porosidad , Prótesis e Implantes , Propiedades de Superficie , Ratas Sprague-Dawley , Masculino , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacologíaRESUMEN
In the field of orthopedics, surgeons have long been facing the challenge of loosening of external fixation screws due to inherent material characteristics. Despite Polyetheretherketone (PEEK) being employed as an orthopedic implant material for many years, its bio-inert nature often hinders bone healing due to the limited bioactivity, which restricts its clinical applications. Herein, a new type of orthopedic implant (Sr-SPK) was developed by introducing strontium (Sr)-doped mesoporous bioactive glass (Sr-MBG) onto the surface of PEEK implants through a simple and feasible method. In vitro experiments revealed that Sr-SPK effectively promotes osteogenic differentiation while concurrently suppressing the formation of osteoclasts. The same results were validated in vivo with Sr-SPK significantly improving bone integration. Upon investigation, it was found that Sr-SPK promotes adhesion among bone marrow mesenchymal stem cells (BMSCs) thereby promoting osteogenesis by activating the regulation of actin cytoskeletal and focal adhesion pathways, as identified via transcriptome analysis. In essence, these findings suggest that the newly constructed Sr-doped biofunctionalized PEEK implant developed in this research can promote osteoblast differentiation and suppress osteoclast activity by enhancing cell adhesion processes. These results underline the immense potential of such an implant for wide-ranging clinical applications in orthopedics.
Asunto(s)
Benzofenonas , Adhesión Celular , Vidrio , Cetonas , Células Madre Mesenquimatosas , Oseointegración , Osteogénesis , Polietilenglicoles , Polímeros , Estroncio , Estroncio/farmacología , Estroncio/química , Oseointegración/efectos de los fármacos , Polímeros/química , Polímeros/farmacología , Adhesión Celular/efectos de los fármacos , Cetonas/química , Cetonas/farmacología , Polietilenglicoles/química , Polietilenglicoles/farmacología , Animales , Osteogénesis/efectos de los fármacos , Vidrio/química , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Diferenciación Celular/efectos de los fármacos , Propiedades de Superficie , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/química , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteoclastos/citología , Ratones , Células Cultivadas , Tamaño de la PartículaRESUMEN
The chemicals formed from antipyrines are flexible organic building blocks that are employed in the development of pharmaceuticals. By diazotizing (4-arylazo-3-hydroxy-2-thienyl) 4-antipyrine ketones 1a, 1b and 1c and (4-arylazo-3-methyl-2-thienyl) 4-antipyrine ketones (2a, 2b and 2c) further replaced with six other coupling components, a broad spectrum of hybrid molecules have been created. Mass spectra, NMR, FTIR, and elemental analyses have all been used to confirm the structures of the synthesised compounds. The antimicrobial screening was investigated by agar well diffusion and diluting the broth technique against both Gram-negative and positive-tested bacterial strains. (3-methyl-5-(phenylamino)-4-(4-tolylazo)-2-thienyl) 4-antipyrine ketone (2a) was found to be superior to Ciprofloxacin against test strains: Acinetobacter sp (34.33±1.15â mm), Listeria monocytogenes (29.33±1.15â mm) and Streptococcus sp. (19.33±1.15 mm). Also, good to moderate activities were expressed as minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) which were recorded at 9±1 to 59.67±4.51â µg/mL and 16±4 to >512â µg/mL, respectively, using compounds 2a, 2b, and 2c. MBC/MIC ratio showed, that only, 2a and 2b have a bactericidal effect but other antipyrines with bacteriostatic strength. To conclude, it was suggested that the use of these novel synthesized (4-arylazo-3-methyl-2-thienyl) 4-antipyrine ketone derivatives molecules as a new chemical class of antimicrobial agents to perform new drug discovery in pharmaceutical preparations and medicinal research.
Asunto(s)
Antibacterianos , Diseño de Fármacos , Cetonas , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Cetonas/química , Cetonas/farmacología , Cetonas/síntesis química , Antipirina/farmacología , Antipirina/química , Antipirina/análogos & derivados , Antipirina/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacosRESUMEN
Disulfide bond protein A (DsbA) is an oxidoreductase enzyme that catalyzes the formation of disulfide bonds in Gram-negative bacteria. In Escherichia coli, DsbA (EcDsbA) is essential for bacterial virulence, thus inhibitors have the potential to act as antivirulence agents. A fragment-based screen was conducted against EcDsbA and herein we describe the development of a series of compounds based on a phenylthiophene hit identified from the screen. A novel thiol reactive and "clickable" ethynylfluoromethylketone was designed for reaction with azide-functionalized fragments to enable rapid and versatile attachment to a range of fragments. The resulting fluoromethylketone conjugates showed selectivity for reaction with the active site thiol of EcDsbA, however unexpectedly, turnover of the covalent adduct was observed. A mechanism for this turnover was investigated and proposed which may have wider ramifications for covalent reactions with dithiol-disulfide oxidoreducatases.
Asunto(s)
Proteínas de Escherichia coli , Escherichia coli , Cetonas , Escherichia coli/enzimología , Escherichia coli/efectos de los fármacos , Cetonas/química , Cetonas/farmacología , Cetonas/síntesis química , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/antagonistas & inhibidores , Proteínas de Escherichia coli/química , Proteína Disulfuro Isomerasas/antagonistas & inhibidores , Proteína Disulfuro Isomerasas/metabolismo , Estructura Molecular , Relación Estructura-Actividad , Especificidad por Sustrato , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis químicaRESUMEN
It has been demonstrated that isoflurane-induced anesthesia can increase the blood glucose level, leading to hyperglycemia and several adverse effects. The administration of a mix of ketone diester (KE) and medium-chain triglyceride (MCT) oil, named KEMCT, abolished the isoflurane-anesthesia-induced increase in blood glucose level and prolonged the recovery time from isoflurane anesthesia in a male preclinical rodent model, Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. While most preclinical studies use exclusively male animals, our previous study on blood glucose changes in response to KEMCT administration showed that the results can be sex-dependent. Thus, in this study, we investigated female WAG/Rij rats, whether KEMCT gavage (3 g/kg/day for 7 days) can change the isoflurane (3%)-anesthesia-induced increase in blood glucose level and the recovery time from isoflurane-evoked anesthesia using the righting reflex. Moreover, KEMCT-induced ketosis may enhance both the extracellular level of adenosine and the activity of adenosine A1 receptors (A1Rs). To obtain information on the putative A1R mechanism of action, the effects of an A1R antagonist, DPCPX (1,3-dipropyl-8-cyclopentylxanthine; intraperitoneal/i.p. 0.2 mg/kg), on KEMCT-generated influences were also investigated. Our results show that KEMCT supplementation abolished the isoflurane-anesthesia-induced increase in blood glucose level, and this was abrogated by the co-administration of DPCPX. Nevertheless, KEMCT gavage did not change the recovery time from isoflurane-induced anesthesia. We can conclude that intragastric gavage of exogenous ketone supplements (EKSs), such as KEMCT, can abolish the isoflurane-anesthesia-induced increase in blood glucose level in both sexes likely through A1Rs in WAG/Rij rats, while recovery time was not affected in females, unlike in males. These results suggest that the administration of EKSs as an adjuvant therapy may be effective in mitigating metabolic side effects of isoflurane, such as hyperglycemia, in both sexes.
Asunto(s)
Anestésicos por Inhalación , Glucemia , Isoflurano , Cetonas , Animales , Femenino , Isoflurano/farmacología , Isoflurano/administración & dosificación , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Ratas , Cetonas/administración & dosificación , Cetonas/farmacología , Anestésicos por Inhalación/administración & dosificación , Anestésicos por Inhalación/farmacología , Ratas Wistar , Suplementos Dietéticos , Triglicéridos/sangre , Triglicéridos/administración & dosificación , Masculino , Adenosina/farmacología , Adenosina/administración & dosificación , Anestesia/métodosRESUMEN
The discovery of structurally distinct leads is imperative in modern agrochemical science. Inspired by eudistomins Y and the framework-related pharmaceuticals, aryl heteroaryl ketone was drawn as a common model intriguing the design and divergent synthesis of 14 kinds of heteroaryl ketones aligned with their oxime derivatives. Antifungal function-oriented phenotypical screen protruded benzothiazolyl-phenyl oxime 5a as a promising model, and the concomitant modification led to benzothiazolyl oxime 5am (EC50 = 5.17 µM) as a superior lead than fluoxastrobin (EC50 = 7.54 µM) against Sclerotinia sclerotiorum. Scaffold hopping of the phenyl subunit identified benzothiazolyl-pyridyl oxime as a novel antifungal scaffold accompanied by acquiring oxime 5bm with remarkable activity (EC50 = 3.57 µM) against Pyricularia oryzae. Molecular docking showed that candidate 5am could form more hydrogen bonds with the amino acid residues of actin than metrafenone. This compound also demonstrated better curative efficacy than that of fluoxastrobin and metrafenone in controlling the plant disease caused by S. sclerotiorum. These results rationalize the discovery of antifungal candidates based on aryl heteroaryl ketone.
Asunto(s)
Ascomicetos , Diseño de Fármacos , Fungicidas Industriales , Cetonas , Simulación del Acoplamiento Molecular , Enfermedades de las Plantas , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Fungicidas Industriales/síntesis química , Ascomicetos/efectos de los fármacos , Ascomicetos/química , Cetonas/química , Cetonas/farmacología , Relación Estructura-Actividad , Enfermedades de las Plantas/microbiología , Estructura Molecular , Oximas/química , Oximas/farmacología , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/síntesis químicaRESUMEN
Polyetheretherketone (PEEK) is considered as an excellent biomaterial for bone grafting and connective tissue replacement. The clinical potential is, however, limited by its bioinertness, poor osteoconduction, and weak antibacterial activity. These disadvantages can be overcome by introducing suitable additives to produce mineral-polymer composites or coatings. In this work, a PEEK-based bioactive composite has been obtained by blending the polymer with magnesium phosphate (Mg3(PO4)2) particles in amounts ranging from 1 to 10 wt.% using the hot press technique. The obtained composite exhibited improved mechanical and physical properties, above the lower limits set for bone engineering applications. The tested grafts were found to not induce cytotoxicity. The presence of magnesium phosphate induced the mineralisation process with no adverse effects on the expression of the marker crucial for osteoblastic differentiation. The most promising results were observed in the grafts containing 1 wt.% of magnesium phosphate embedded within the PEEK matrix. The improved bioactivity of grafts, together with suitable physical-chemical and mechanical properties, indicate this composite as a promising orthopaedic implant material.
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Benzofenonas , Materiales Biocompatibles , Cetonas , Fosfatos , Polietilenglicoles , Polímeros , Cetonas/química , Cetonas/farmacología , Polímeros/química , Polietilenglicoles/química , Materiales Biocompatibles/química , Fosfatos/química , Humanos , Compuestos de Magnesio/química , Compuestos de Magnesio/farmacología , Ensayo de Materiales , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismoRESUMEN
Polyetheretherketone (PEEK), particularly its sulfonated form (SPEEK), has emerged as a promising synthetic biomaterial for artificial bone implants, providing an alternative to conventional titanium metal. However, postoperative infections pose a critical challenge, driven by diverse and antibiotic-resistant bacteria. To address this issue, we propose the modification of the SPEEK surface using a thin graphene oxide (GO) film containing silver (Ag) ions. The resulting coating exhibits substantial antibacterial effects against various pathogens, including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans. Experimental assessments elucidate the coating's impact on bacterial adhesion, biofilm formation, and morphology. The results suggest that hindered bacterial growth stems from reduced biofilm production and the controlled release of Ag ions facilitated by the GO coating. The Ag/GO-SPEEK material holds promise as a bioactive implant, addressing the challenges associated with bacterial targeting in bone tissue engineering applications.
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Antibacterianos , Benzofenonas , Grafito , Ensayo de Materiales , Pruebas de Sensibilidad Microbiana , Polietilenglicoles , Polímeros , Plata , Grafito/química , Grafito/farmacología , Plata/química , Plata/farmacología , Benzofenonas/química , Benzofenonas/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Polímeros/química , Polímeros/farmacología , Polietilenglicoles/química , Polietilenglicoles/farmacología , Staphylococcus aureus/efectos de los fármacos , Cetonas/química , Cetonas/farmacología , Tamaño de la Partícula , Candida albicans/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Biopelículas/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacosRESUMEN
Patient-specific fabrication of scaffold/implant requires an engineering approach to manufacture the ideal scaffold. Herein, we design and 3D print scaffolds comprised of polyether-ether-ketone (PEEK) and sodium-carboxymethyl cellulose (Na-CMC). The fabricated scaffold was dip coated with Zn and Mn doped bioactive glass nanoparticles (Zn-Mn MBGNs). The synthesized ink exhibit suitable shear-thinning behavior for direct ink write (DIW) 3D printing. The scaffolds were crafted with precision, featuring 85% porosity, 0.3 mm layer height, and 1.5 mm/s printing speed at room temperature. Scanning electron microscopy images reveal a well-defined scaffold with an average pore size of 600 ± 30 µm. The energy dispersive X-ray spectroscopy analysis confirmed a well dispersed/uniform coating of Zn-Mn MBGNs on the PEEK/Na-CMC scaffold. Fourier transform infrared spectroscopy approved the presence of PEEK, CMC, and Zn-Mn MBGNs. The tensile test revealed a Young's modulus of 2.05 GPa. Antibacterial assays demonstrate inhibition zone against Staphylococcus aureus and Escherichia Coli strains. Chick Chorioallantoic Membrane assays also present significant angiogenesis potential, owing to the antigenic nature of Zn-Mn MBGNs. WST-8 cell viability assays depicted cell proliferation, with a 103% viability after 7 days of culture. This study suggests that the PEEK/Na-CMC scaffolds coated with Zn-Mn MBGNs are an excellent candidate for osteoporotic fracture treatment. Thus, the fabricated scaffold can offer multifaceted properties for enhanced patient outcomes in the bone tissue regeneration.
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Benzofenonas , Carboximetilcelulosa de Sodio , Vidrio , Cetonas , Manganeso , Nanopartículas , Polietilenglicoles , Polímeros , Impresión Tridimensional , Staphylococcus aureus , Andamios del Tejido , Zinc , Porosidad , Benzofenonas/química , Vidrio/química , Cetonas/química , Cetonas/farmacología , Andamios del Tejido/química , Staphylococcus aureus/efectos de los fármacos , Carboximetilcelulosa de Sodio/química , Nanopartículas/química , Zinc/química , Zinc/farmacología , Polímeros/química , Manganeso/química , Polietilenglicoles/química , Antibacterianos/química , Antibacterianos/farmacología , Animales , Escherichia coli/efectos de los fármacos , Ensayo de Materiales , HumanosRESUMEN
The PI3K pathway regulates essential cellular functions and promotes chemotherapy resistance. Activation of PI3K pathway signaling is commonly observed in triple-negative breast cancer (TNBC). However previous studies that combined PI3K pathway inhibitors with taxane regimens have yielded inconsistent results. We therefore set out to examine whether the combination of copanlisib, a clinical grade pan-PI3K inhibitor, and eribulin, an antimitotic chemotherapy approved for taxane-resistant metastatic breast cancer, improves the antitumor effect in TNBC. A panel of eight TNBC patient-derived xenograft (PDX) models was tested for tumor growth response to copanlisib and eribulin, alone or in combination. Treatment-induced signaling changes were examined by reverse phase protein array, immunohistochemistry (IHC) and 18F-fluorodeoxyglucose PET (18F-FDG PET). Compared with each drug alone, the combination of eribulin and copanlisib led to enhanced tumor growth inhibition, which was observed in both eribulin-sensitive and -resistant TNBC PDX models, regardless of PI3K pathway alterations or PTEN status. Copanlisib reduced PI3K signaling and enhanced eribulin-induced mitotic arrest. The combination enhanced induction of apoptosis compared with each drug alone. Interestingly, eribulin upregulated PI3K pathway signaling in PDX tumors, as demonstrated by increased tracer uptake by 18F-FDG PET scan and AKT phosphorylation by IHC. These changes were inhibited by the addition of copanlisib. These data support further clinical development for the combination of copanlisib and eribulin and led to a phase I/II trial of copanlisib and eribulin in patients with metastatic TNBC. SIGNIFICANCE: In this research, we demonstrated that the pan-PI3K inhibitor copanlisib enhanced the cytotoxicity of eribulin in a panel of TNBC PDX models. The improved tumor growth inhibition was irrespective of PI3K pathway alteration and was corroborated by the enhanced mitotic arrest and apoptotic induction observed in PDX tumors after combination therapy compared with each drug alone. These data provide the preclinical rationale for the clinical testing in TNBC.